The WDR35 gene is located on chromosome 2 at 2p24.1 and encodes IFT121 protein, which forms part of intraflagellar transport (IFT) complex A (IFT-A) that combines with IFT complex B (IFT-B) to form an IFT particle that is important in the assembly and maintenance of cilia. WDR35 was first reported in relation to autosomal recessive cranioectodermal dysplasia (CED) , also known as Sensenbrenner syndrome, a rare multiple anomaly syndrome with distinctive craniofacial findings (forehead bossing, dolichocephaly), metaphyseal dysplasia (short limbs, small thorax), ectodermal anomalies (sparse hair, small and missing teeth, short nails), connective tissue abnormalities (loose skin, joint laxity), retinal dystrophy, and chronic renal and liver disease in 2010 (Gilissen et al., 2010, PMID: 20817137). Additionally, the Craniofacial Malformations GCEP has reviewed the craniofacial findings and agrees with the summary. Evidence supporting this gene-disease relationship includes case-level and experimental data. Biallelic variants in WDR35 (including nonsense, frameshift, splice, and missense variants) were identified in at least 12 patients with clinical features suggestive of CED (PMID: 20817137; Hoffer et al., 2013, PMID: 22486404; Smith et al., 2016, PMID: 26691894; Antony et a., 2017, PMID: 28870638; Walczak-Sztulpa et al., 2017, PMID: 28332779; Walczak-Sztulpa et al., 2018, PMID: 29134781; Walczak-Sztulpa et al., 2021, PMID: 29134781). At least 18 unique variants (missense, nonsense, frameshift, small deletions) have been reported in humans. This gene-disease relationship is supported by protein interaction studies and rescue of phenotype with cell culture models (Caparros-Martin et al., 2015, PMID: 25908617; Takahara et al., 2018, PMID: 29220510). In summary, the WDR35 gene is definitely associated with cranioectodermal dysplasia (autosomal recessive inheritance). This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Syndromic Disorders Gene Curation Expert Panel on the meeting date 7.27.2021 (SOP Version 8).
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